Bone marrow mesenchymal stem cell donors with a high body mass index display elevated endoplasmic reticulum stress and are functionally impaired

J Cell Physiol. 2018 Nov;233(11):8429-8436. doi: 10.1002/jcp.26804. Epub 2018 May 24.


Bone marrow mesenchymal stem cells (BM-MSCs) are promising candidates for regenerative medicine purposes. The effect of obesity on the function of BM-MSCs is currently unknown. Here, we assessed how obesity affects the function of BM-MSCs and the role of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) therein. BM-MSCs were obtained from healthy donors with a normal (<25) or high (>30) body mass index (BMI). High-BMI BM-MSCs displayed severely impaired osteogenic and diminished adipogenic differentiation, decreased proliferation rates, increased senescence, and elevated expression of ER stress-related genes ATF4 and CHOP. Suppression of ER stress using tauroursodeoxycholic acid (TUDCA) and 4-phenylbutyrate (4-PBA) resulted in partial recovery of osteogenic differentiation capacity, with a significant increase in the expression of ALPL and improvement in the UPR. These data indicate that BMI is important during the selection of BM-MSC donors for regenerative medicine purposes and that application of high-BMI BM-MSCs with TUDCA or 4-PBA may improve stem cell function. However, whether this improvement can be translated into an in vivo clinical advantage remains to be assessed.

Keywords: 4-phenylbutyrate; body mass index; bone marrow mesenchymal stem cells; endoplasmic reticulum stress; tauroursodeoxycholic acid.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 4 / genetics
  • Adipogenesis / drug effects
  • Adolescent
  • Adult
  • Alkaline Phosphatase / genetics
  • Body Mass Index*
  • Cell Differentiation / drug effects
  • Cell Proliferation / drug effects
  • Cellular Senescence / drug effects
  • Child
  • Endoplasmic Reticulum Stress / genetics*
  • Female
  • Gene Expression Regulation, Developmental / drug effects
  • Humans
  • Male
  • Mesenchymal Stem Cell Transplantation
  • Mesenchymal Stem Cells / cytology
  • Mesenchymal Stem Cells / metabolism*
  • Mesenchymal Stem Cells / pathology
  • Middle Aged
  • Obesity / genetics
  • Obesity / metabolism*
  • Obesity / pathology
  • Osteogenesis / drug effects
  • Phenylbutyrates / pharmacology
  • Regenerative Medicine
  • Taurochenodeoxycholic Acid / pharmacology
  • Tissue Donors
  • Transcription Factor CHOP / genetics
  • Unfolded Protein Response / genetics
  • Young Adult


  • ATF4 protein, human
  • DDIT3 protein, human
  • Phenylbutyrates
  • Activating Transcription Factor 4
  • Transcription Factor CHOP
  • Taurochenodeoxycholic Acid
  • ursodoxicoltaurine
  • 4-phenylbutyric acid
  • ALPL protein, human
  • Alkaline Phosphatase